1. Field of the Invention
The present invention relates to a method for making and administering a blinded oral dosage form and the blinded oral dosage form therefor, used for disguising the identity of tableted medications.
2. Description of the Prior Art
Over the years, various methods and devices have been used to compare one medication with another to determine the relative safety and/or efficacy of the medication. It is a common practice to disguise the medications in order to prevent any prejudice from investigators administering the drugs and subjects ingesting the drugs. Disguising medications from investigators administering or subjects ingesting the medication is commonly referred to as "blinding".
Tableted medications are normally "blinded" by placing the medication in elongated cylindrical, i.e., tubular, opaque gelatin capsules along with inactive packing materials. In this way, none of the tableted medications can be identified by the investigators administering the medication or subjects ingesting the medication. However, conventional "blinding" procedures using elongated cylindrical gelatin capsules have specific limitations when using certain tablets since the diameter of the tablet is often very large in relation to the diameter of the capsule.
Elongated cylindrical, or tubular, gelatin capsules may be purchased in standard sizes having a body portion and a cap portion. The capsules typically have an elongated cylindrical shape with rounded ends that facilitate the swallowing of the capsule. Standard elongated cylindrical capsules may be purchased in various sizes. However, the diameter of the capsule is typically small in relation to the length or height of the capsule.
For example, ELANCO Qualicaps.TM., which are typical of the industry, are available in the following sizes: 000, 00, 0EL, 0, 1, 2, 3, 4 and 5. The dimensions of these capsules are provided in the following table.
__________________________________________________________________________ DIMENSIONS OF ELANCO QUALICAPS .TM. CAP BODY CAP BODY FILL.sup.1 DIAMETER DIAMETER LENGTH LENGTH LENGTH SIZE (MM) (MM) (MM) (MM) (MM) __________________________________________________________________________ 000 9.88 9.5 13.1 22.0 26.1 00 8.51 8.15 11.7 20.2 23.5 0EL 7.63 7.33 12.0 20.7 24.0 0 7.63 7.33 10.9 18.5 21.8 1 6.90 6.62 9.7 16.5 19.5 2 6.35 6.07 8.9 15.1 17.8 3 5.82 5.56 7.9 13.3 15.8 4 5.32 5.06 7.2 12.3 14.5 5 4.9 4.67 6.0 9.1 11.7 __________________________________________________________________________ .sup.1 FILL LENGTH is the recommended filled joined length of ELANCO POSILOK .TM. capsules which is controlled by the location of the locking features on the cap and body.
As listed, such capsules have a length to diameter ratio of well over two but less than three.
In contrast, tableted medications commonly used in the pharmaceutical industry are manufactured in various shapes and sizes. One common shape used for tableted medications is the disk-shaped tablet. The diameter of these tablets is usually large in relation to the length or height of the tablet. Consequently, when investigating or comparing medications, one of which is in a tablet form, the investigator must obtain a capsule large enough to facilitate the diameter of the largest tablet used in the study. That is, the cylindrical or tubular capsule into which the tableted medication must be placed for purposes of blinding, must have a larger diameter than the diameter of the tablet. Alternatively, the tableted medication must be broken into small pieces or particles to place the medication into the capsule.
A standard elongated capsule having a diameter larger than the diameter of the tableted medication has a length at least two times longer than the diameter of the tableted medication. For example, a tableted medication having a diameter of 9 millimeters would have to be encapsulated in an 000 ELANCO Qualicap.TM.. The fill length of the ELANCO Qualicap.TM. is 26.1 millimeters. Consequently, the standard elongated cylindrical capsules are much longer than necessary.
One concern that arises with respect to the ingestion of medication is that the elongated cylindrical capsules large enough to encapsulate various tableted medications are so large that they are not as easily swallowed as the tableted medication itself. This is especially important when administering such medication to infants, children and the elderly who often have difficulty swallowing medication.
Another concern that arises with respect to the ingestion of medication is that elongated cylindrical capsules can accidentally be swallowed sideways which causes the capsule to enter the esophagus lengthwise. This produces difficulty in swallowing and significant discomfort to the subject ingesting the capsule. This is especially important when cylindrical-shaped capsules are presented to animals as it is sometimes necessary to push the capsule down the throat of the animal.
Another concern that arises with respect to the ingestion of medication is that there are no readily available cylindrical capsules that may be used to encapsulate tableted medications having a large diameter. For example, a tableted medication having a diameter of 10 millimeters or more could not be encapsulated in even the largest ELANCO Qualicap.TM. which has a diameter of 9.5 millimeters. Tableted medications having a diameter of 10 millimeters or more are common. Such medications are illustrated in the Physician's Desk Reference, 43rd Edition, Medical Economics Company, Inc., Oradell, N.J. (1989) and in The Family physician's Compendium of Drug Therapy, McGraw-Hill Book Company, New York (1988) both of which contain actual size, full-color reproductions of various medications available from various manufacturers.
Of course, tableted medications could be broken into smaller pieces or used in smaller sizes; however, breaking tableted medications or using them in smaller sizes affects the actual kinetics of medication. In particular, when tablets are broken up into smaller sizes there is more surface area for dissolution and absorption of the medication. Furthermore, many tableted medications have various coatings which will become ineffective if destroyed. Consequently, the integrity of the investigation or comparison is compromised when breaking up the tableted medications.
Thus, in the majority of research studies, a "double-dummy" approach is used when encapsulation is not practical. The "double-dummy" approach could best be exemplified in a study in which two or more tablets of varying size (for instance, one large and one small) are compared for safety or efficacy. When the larger of two tablets is of too great a diameter to be placed inside the standard elongated capsule, it becomes necessary to produce placebos for both the large and small tablets. The "double-dummy" procedure requires the subject to ingest two tablets (one active and one placebo). Therefore, when taking a large tablet as active medication, the subject must also take a smaller tablet as a placebo and vice versa. This method allows the investigator and the subject taking the medicine to be blinded as to whether the larger tablet is an active medication or, alternatively, a placebo.
Many variations of the "double-dummy" procedure exist. However, all variations require the expense of developing placebos identical to test medications or obtaining the placebo from the manufacturer of the active product. Furthermore, it should be noted that the use of two or more tablets in a "double-dummy" procedure requires the subject to ingest several pills at each dosing period. The ingestion of two or more pills inherently results in a significant placebo effect which may increase (or, alternatively, decrease) the perceived efficacy (or side effect) profile of the study medication. In addition, ingesting multiple pills may affect the actual kinetics of the study medication.
While various unconventionally shaped capsules are known in the art, the capsules are either not used to blind tableted medications and/or are not convenient for blinding tableted medications. Such various unconventionally shaped capsules are disclosed in U.S. Pat. No. 462,990; 710,060; 730,643; 1,087,843; 1,148,621; 2,196,283; and 4,774,092.
U.S. Pat. No. 462,990 discloses a capsule consisting of a soluble shell or casing formed integrally with a soluble partition to provide separated chambers for different kinds of medicine. This patent does not disclose a method for blinding tableted medications. In fact, the capsules are not suitable for blinding tableted medications since they are not constructed in a manner that permits tableted medication of various sizes and shapes to be placed therein.
U.S. Pat. No. 710,060 discloses a capsule in which one piece is provided with a double wall construction and the other piece a single wall construction. The patent mentions nothing with respect to placing a tableted medication within the capsule.
U.S. Pat. No. 730,643 discloses a tableted medication contained within a gelatin casing. The tableted medication is enclosed within the casing along with a liquid ingredient for introducing the solid and liquid simultaneously. The device shown in U.S. Pat. No. 730,643 is not acceptable for blinding procedures since the casing containing the liquid and solid ingredients is formed with various presses and dies resulting in an integrally formed-one piece sphere.
U.S. Pat. No. 3,536,074 discloses a tableted medication within a liquid impervious frangible sac. The tableted medication is enclosed within the frangible sac along with a liquid ingredient to assist in the swallowing of the tableted medication. The device shown in U.S. Pat. No. 3,536,074 is not acceptable for blinding procedures since the frangible sac containing the liquid and solid ingredients is an integrally-formed one piece unit.
The devices disclosed in U.S. Pat. Nos. 730,643 and 3,536,074 are unacceptable for blinding studies since the manufacture of such devices requires manufacturing equipment for placing the tablet and liquid within the capsule and for sealing the capsule.
The above-described methods and devices are intended to provide a means for "blinding" medications from investigators and subjects taking the medications. However, as described above, there are many disadvantages associated with these methods. Such disadvantages include the fact that elongated cylindrical or tubular shaped capsules readily available to those in the art are not convenient for disguising many tableted medications due to their inability to contain many of the larger tableted medications and the unsatisfactory nature of the alternative methods which are commonly utilized.
Thus, there remains a long felt need in the art for an improved method and device for "blinding" tableted medications containing an active substance. Such method would facilitate the investigation of various medications to determine their physiological or pharmacological effect as well as to compare the safety and/or efficacy of the medications with other medications.